A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

  • Cell Chem Biol. 2021 Jun 17;28(6):835-847.e5. doi: 10.1016/j.chembiol.2021.02.006.
Duncan E Scott  1 ,  Nicola J Francis-Newton  2 ,  May E Marsh  3 ,  Anthony G Coyne  1 ,  Gerhard Fischer  3 ,  Tommaso Moschetti  3 ,  Andrew R Bayly  1 ,  Timothy D Sharpe  3 ,  Kalina T Haas  2 ,  Lorraine Barber  2 ,  Chiara R Valenzano  1 ,  Rajavel Srinivasan  1 ,  David J Huggins  4 ,  Miyoung Lee  2 ,  Amy Emery  2 ,  Bryn Hardwick  2 ,  Matthias Ehebauer  3 ,  Claudio Dagostin  1 ,  Alessandro Esposito  2 ,  Luca Pellegrini  3 ,  Trevor Perrior  5 ,  Grahame McKenzie  2 ,  Tom L Blundell  3 ,  Marko Hyvönen  6 ,  John Skidmore  7 ,  Ashok R Venkitaraman  8 ,  Chris Abell  1
Affiliations
  • 1. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • 2. Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
  • 3. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
  • 4. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
  • 5. Excellium Consulting, Brook Farm Barn, Lackford, Bury St Edmunds IP28 6HL, UK.
  • 6. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: [email protected].
  • 7. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].
  • 8. Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK. Electronic address: [email protected].
PMID: 33662256 DOI: 10.1016/j.chembiol.2021.02.006
Abstract

BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for Cancer therapy.

Keywords
BRCA2; DNA repair; RAD51; RAD51 inhibitor; cancer therapy; homologous recombination; protein-protein interaction inhibition; radiosensitizer; structure-guided drug discovery.
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